CN114539252A - 2, 3-dihydroquinoline-4-ketone bioactive skeleton and synthesis method and application thereof - Google Patents

2, 3-dihydroquinoline-4-ketone bioactive skeleton and synthesis method and application thereof Download PDF

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CN114539252A
CN114539252A CN202210410052.0A CN202210410052A CN114539252A CN 114539252 A CN114539252 A CN 114539252A CN 202210410052 A CN202210410052 A CN 202210410052A CN 114539252 A CN114539252 A CN 114539252A
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李爱国
王亮
解容浩
尹相莹
陈宁
梁国磊
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Abstract

The invention discloses a 2, 3-dihydroquinoline-4-ketone bioactive skeleton and a synthesis method and application thereof, belonging to the technical field of chemical synthesis. The technical scheme is as follows: the structural formula of the 2, 3-dihydroquinoline-4-ketone bioactive framework is as follows:
Figure DDA0003603331370000011
in the formula, R1Is any one of nitrogen heterocycle and ethyl; r2Is any one of nitrogen heterocycle and methyl; r3Is any one of hydrogen atom and methoxyl; r4Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl. The method has the advantages of mild reaction conditions, good substrate universality, step economy, atom economy, high chemical selectivity, few byproducts, high yield, low raw material cost and the like, and is convenient for future industrial application.

Description

2, 3-dihydroquinoline-4-ketone bioactive skeleton and synthesis method and application thereof
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a 2, 3-dihydroquinolin-4-one bioactive skeleton and a synthesis method and application thereof.
Background
The 2, 3-dihydroquinoline-4-ketone bioactive skeleton compound is an important heterocyclic compound and has wide application in the fields of malaria resistance, cancer resistance, pain relief and the like. For example, 2-ferrocene-2, 3-dihydroquinolin-4-one was found to have good antimalarial activity by Angela Patti topic group of CNR Biochemical research institute, Italy, 2012. 2011, Chul Min Park topic group of Korean institute of chemical and technology, discovered 1- (arylsulfonyl) -2, 3-dihydroquinolin-4-one derivatives against 5-HT6Exhibit high binding affinity (IC)508nM) has good selectivity for serotonin and dopamine, showing excellent anticancer activity. In 1965, 1,2,2,3, 3-pentamethylquinolin-4-one was found to have a significant analgesic effect on mice by Atwal subject group of university of Illinois, USA. The compounds are all 2, 3-dihydroquinoline-4-ketone derivatives. In view of the importance of the 2, 3-dihydroquinolin-4-one skeleton in the medical field, toThe efficient synthesis of the skeleton becomes a research hotspot in the field of organic synthesis.
Figure BDA0003603331350000011
The task group Tamio Hayashi of Kyoto university, Japan, 2005 synthesized a 2-aryl-2, 3-dihydroquinolin-4-one skeleton by rhodium-catalyzed 1,4 addition reaction of aryl zinc (org. Lett.2005,7, 5317-one 5319). The reaction requires a noble metal rhodium catalyst, which increases the reaction cost.
Figure BDA0003603331350000012
In 2015, the TakahikoAkiyama project group at Japan institute of learning university reported a method for asymmetric synthesis of 2, 3-dihydroquinolin-4-one skeleton catalyzed by chiral phosphoric acid (org. Lett.2015,17, 3202-substituted 3205), which is expensive in chiral phosphoric acid and long in reaction time.
Figure BDA0003603331350000021
In 2010, the project group of SergeyA.Kozmin, American university of Chicago, utilizes quinolone and ketene to generate 2, 3-dihydroquinolin-4-one skeleton through cycloaddition under the catalysis of trifluoroacetic acid, the reaction uses strong acid trifluoroacetic acid as a catalyst, and an N-H bond on the quinolone needs to be protected and deprotected, thereby increasing the reaction steps.
Figure BDA0003603331350000022
Although the reaction can synthesize the 2, 3-dihydroquinolin-4-one skeleton with high efficiency, the application of the reactions is greatly limited, especially the application of the reactions in the pharmaceutical production industry is limited, because the expensive metal catalyst or the reaction has long reaction time, long route and poor substrate universality.
Therefore, how to efficiently construct the 2, 3-dihydroquinolin-4-one skeleton by using cheap and easily-obtained raw materials and green and mild reaction conditions is a problem which needs to be solved at present.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the invention overcomes the defects of the prior art, provides the 2, 3-dihydroquinolin-4-one bioactive framework, and the synthesis method and the application thereof, has the advantages of mild reaction conditions, good substrate universality, step economy, atom economy, high chemical selectivity, few byproducts, high yield, low raw material cost and the like, and is convenient for future industrial application.
The technical scheme of the invention is as follows:
in a first aspect, the present invention provides a 2, 3-dihydroquinolin-4-one bioactive scaffold having the formula:
Figure BDA0003603331350000023
in the formula, R1Is any one of nitrogen heterocycle and ethyl; r2Is any one of nitrogen heterocycle and methyl; r3Is any one of hydrogen atom and methoxyl; r4Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.
In a second aspect, as shown in fig. 1, the present invention also provides a method for synthesizing the above 2, 3-dihydroquinolin-4-one bioactive skeleton, comprising the steps of:
uniformly mixing 2-aminobenzoyl methyl acetate compounds and formaldehyde compounds in a molar ratio of 1:1.2-1:1.5 in a solvent, and reacting at 80-120 ℃ to obtain 2, 3-dihydroquinolin-4-one compounds;
wherein, the structural formula of the 2-aminobenzoyl methyl acetate compound is as follows:
Figure BDA0003603331350000031
wherein R is1Is a nitrogen heterocycleAny one of ethyl and ethyl; r2Is any one of nitrogen heterocycle and methyl; r3Is any one of hydrogen atom and methoxyl;
wherein, the structural formula of the formaldehyde compound is as follows:
Figure BDA0003603331350000032
wherein R is4Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.
The reaction conditions can be detected by thin layer chromatography, and purification is carried out after the reaction is finished to obtain the purified product of the 2, 3-dihydroquinolin-4-one compound.
The reaction process is as follows:
2-aminobenzoyl methyl acetate compounds and formaldehyde compounds are subjected to Knoevenagel condensation reaction to form intermediate product electron-deficient olefin, and the electron-deficient olefin is used as a driving force to initiate intramolecular [1,7]]-hydroshifting/cyclizing to form the final 2, 3-dihydroquinolin-4-one compound. The synthetic route is concretely as follows (2-aminobenzoyl methyl acetate compound)
Figure BDA0003603331350000033
For example):
Figure BDA0003603331350000041
preferably, the solvent is ethanol or 1, 2-dichloroethane; preferably, the solvent is 1, 2-dichloroethane.
Preferably, the solvent is used in an amount of: adding 0.5-2.0mL of solvent into 0.1 mol of 2-aminobenzoyl methyl acetate compound; preferably, 1mL of the solvent is added per 0.1mmol of the methyl 2-aminobenzoylacetate-based compound.
Preferably, adding a catalyst before the reaction, wherein the catalyst is Bronsted acid and Lewis acid; superior foodOptionally, the catalyst is Sc (OTf)3。
Preferably, the catalyst is used in an amount of 10 to 20 mol%.
Preferably, a catalyst carrier is added before the reaction, and the catalyst carrier is
Figure BDA0003603331350000042
And (3) a molecular sieve.
Preferably, the dosage of the catalyst carrier is 6 to 7 times of the mass of the formaldehyde compound.
Preferably, a base is added before the reaction, wherein the base is piperidine and is used in an amount of 4-6 mol%.
The compounds to which the present invention relates may exist in the form of one or more stereoisomers. The various isomers include enantiomers, diastereomers, geometric isomers. It is within the scope of the present invention for these isomers to include mixtures of these isomers.
In a third aspect, the invention also provides an application of the 2, 3-dihydroquinolin-4-one bioactive skeleton synthesized by the synthesis method in anticancer drugs.
Compared with the prior art, the invention has the following beneficial effects:
1. the synthesis reaction realizes the neutral redox tandem Knoevenagel condensation/[ 1,7] -hydrogen migration/cyclization reaction to construct the 2, 3-dihydroquinoline-4-ketone bioactive framework compound under mild conditions, and provides a convenient and simple synthesis method for the 2, 3-dihydroquinoline-4-ketone bioactive framework.
2. The synthetic method has good substrate universality, the substrate substituent can be an electron-withdrawing group or an electron-donating group, and the position of the substituent has no obvious influence on the reaction yield. The invention provides experimental basis for the efficient construction of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton, and has good practical significance and application value.
3. The synthetic method introduces allyl/propargyl into the 3-position of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton, is beneficial to constructing other functional compounds, and lays a foundation for more applications of the 2, 3-dihydroquinoline-4-ketone bioactive skeleton.
4. The synthetic method disclosed by the invention is short in reaction route, only water is contained as a byproduct, the principles of atom economy and environmental protection are met, and the 2, 3-dihydroquinolin-4-one bioactive framework is synthesized in a green and efficient manner.
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FIG. 1 is a scheme of the synthesis process of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.
Example 1
1. This example provides a method for synthesizing a bioactive framework of 2, 3-dihydroquinolin-4-one, comprising the steps of:
taking 0.1mmol of 2-aminobenzoyl methyl acetate compound in a reaction bottle, and sequentially adding 1mL of solvent, 0.15mmol of formaldehyde compound and catalyst. Controlling the reaction temperature of the system, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete. After the reaction is finished, separating and purifying by using a silica gel column, and performing rotary evaporation on the purified product to obtain the target product. The reaction formula is as follows:
Figure BDA0003603331350000051
2. according to the method, 9 groups of parallel test groups are set up, and different catalysts and solvents are respectively adopted. The catalyst is acetic acid/ammonium acetate Ac (OH)/NH respectively4OAc, Piperidine Piperidine, scandium triflate Sc (OTf)3Copper trifluoromethanesulfonate Cu (OTf)2Ytterbium triflate Yb (OTf)3Indium tribromide InBr3FeCl, ferric chloride3Boron trifluoride diethyl etherate BF3.Et2O, trifluoromethanesulfonic acid TfOH; the solvents were toluene, ethanol and 1, 2-dichloroethane, respectively. The specific catalysts, solvent types and corresponding yields used in the test groups are shown in table 1:
TABLE 1 reaction yield of methyl 2-aminobenzoylacetate compound and benzaldehyde under different catalyst conditions
Figure BDA0003603331350000061
Note: the above yields are isolated yields. Different targets are prepared, and the catalytic effect of the catalyst is shown as follows: scandium triflate>Boron trifluoride diethyl etherate>Ferric chloride>Indium tribromide>Trifluoromethanesulfonic acid>Ytterbium trifluoromethanesulfonate>Piperidine; the effect of the above base is shown by piperidine>Triethylamine>Cesium carbonate>Potassium carbonate>Sodium hydroxide; the effect of the catalyst carrier is shown by adding
Figure BDA0003603331350000062
Molecular sieves>Without addition of
Figure BDA0003603331350000063
And (3) a molecular sieve.
According to the analysis of the parallel test results, the following results are obtained: the synthesis reaction of the invention can also be carried out by adding piperidine when ethanol is used as a solvent, but the yield of the product is slightly low; when Bronsted acid and Lewis acid are used as catalysts, the reaction can be carried out, and the catalytic effect of scandium trifluoromethanesulfonate is best; when toluene is used as a solvent, the reaction cannot be carried out; the yield of ethanol as a reaction solvent is slightly low; with 1, 2-dichloroethane asWhen the catalyst is used as a solvent, the highest yield can reach 78 percent by screening the catalyst. The alkali was screened to find that organic bases were more favorable for the reaction than inorganic bases, and piperidine was most effective as the alkali. Without addition of
Figure BDA0003603331350000064
Molecular sieves react poorly and are added
Figure BDA0003603331350000065
Molecular sieves are used to facilitate the reaction.
3. According to the method, the following 9 parallel test groups are set, and different reaction conditions are adopted, such as: different raw material ratios and different reaction temperatures. The catalyst was unified with scandium triflate (20 mol%). The solvent is 1, 2-dichloroethane. The specific settings for the different test groups are shown in table 2:
TABLE 2 reaction yield of methyl 2-aminobenzoylacetate compound and benzaldehyde under different reaction conditions
Figure BDA0003603331350000071
According to the analysis of the parallel test results, the following results are obtained: in the synthesis reaction of the invention, when 1, 2-dichloroethane is used as a solvent, 0.5-2.0mL of solvent is added into each 0.1mmol of 2-aminobenzoyl methyl acetate compound, and the reaction can be carried out; the yield was highest when 1mL of solvent was added per 0.1mmol of methyl 2-aminobenzoylacetate compound; the reaction can be carried out at 80-120 deg.C, with the best conversion effect at 100 deg.C.
In the following examples 2 to 9, reactions were carried out according to the procedure of example 1; in the reaction system, the raw materials of the 2-aminobenzoyl methyl acetate compound and the formaldehyde compound are respectively 0.1mmol and 0.15mmol, and the reaction system is added with 20mol percent of Sc (OTf)3Under the catalysis of scandium trifluoromethanesulfonate, 1mL of 1, 2-dichloroethane is used as a solvent, and the reaction is continuously stirred at the temperature of 100 ℃ until the raw materials are completely reacted, so that corresponding target products are respectively obtained.
Example 2
Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, benzaldehyde
The product is as follows: chemical formula C21H21NO3
Molecular weight: 335.4030
Structural formula (xvi):
Figure BDA0003603331350000072
yield: 79 percent
1H NMR(500MHz,CDCl3)δ7.69(d,J＝7.9Hz,1H),7.38(t,J＝7.7Hz,1H),7.09–7.02(m,3H),6.94(d,J＝4.3Hz,2H),6.67(dd,J＝18.1,10.7Hz,1H),6.57(d,J＝8.4Hz,1H),4.17(dd,J＝9.5,5.6Hz,1H),3.81(s,3H),3.48(ddd,J＝17.8,15.6,8.9Hz,2H),3.32(d,J＝13.7Hz,1H),2.90(d,J＝13.7Hz,1H),2.20–2.12(m,1H),2.09–1.91(m,3H).13C NMR(126MHz,CDCl3)δ190.86(s),171.96(s),148.38(s),136.30(s),135.54(s),130.71(s),129.17(s),127.47(s),126.46(s),118.29(s),116.59(s),112.73(s),77.34(d,J＝6.5Hz),77.11(s),76.86(s),63.44(s),61.74(s),52.60(s),46.83(s),31.74(s),26.23(s),22.95(s).HRMS(ESI):calcd for C21H21NO3Na[M+Na]+:358.3922,found:358.3924。
Example 3
Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, p-nitrobenzaldehyde
The product is as follows: chemical formula C21H20N2O5
Molecular weight: 380.1372
Structural formula (xvi):
Figure BDA0003603331350000081
yield: 72 percent
1H NMR(500MHz,CDCl3)δ7.91(d,J＝8.6Hz,1H),7.67(d,J＝7.9Hz,1H),7.43(t,J＝7.7Hz,1H),7.10(d,J＝8.6Hz,1H),6.72(t,J＝7.5Hz,1H),6.63(d,J＝8.4Hz,1H),4.20(t,J＝7.4Hz,1H),3.83(d,J＝9.0Hz,2H),3.53(ddd,J＝17.4,11.8,7.5Hz,1H),3.43(d,J＝13.5Hz,1H),2.99–2.88(m,1H),2.22(dd,J＝11.5,7.6Hz,1H),2.09–1.95(m,2H).13C NMR(126MHz,CDCl3)δ190.10(s),171.62(s),148.39(s),146.63(s),144.50(s),136.08(s),131.64(s),129.07(s),122.58(s),118.01(s),117.10(s),112.97(s),77.33(s),77.08(s),76.83(s),63.42(s),61.98(s),52.84(s),46.88(s),31.13(s),26.21(s),22.89(s).HRMS(ESI):calcd for C21H20N2O5Na[M+Na]+:403.3892,found:403.3896。
Example 4
Raw materials: n, N-diethylbenzoylacetic acid methyl ester, o-bromobenzaldehyde
The product is as follows: chemical formula C21H22BrNO3
Molecular weight: 416.3150
Structural formula (xvi):
Figure BDA0003603331350000091
yield: 68 percent of
1H NMR(500MHz,CDCl3)δ7.93(dd,J＝7.9,1.5Hz,1H),7.51(dd,J＝13.4,5.2Hz,2H),7.38–7.31(m,1H),7.24(t,J＝7.5Hz,1H),7.06(td,J＝7.9,1.5Hz,1H),6.68(t,J＝7.4Hz,1H),6.59(d,J＝8.5Hz,1H),5.29(s,1H),4.12(q,J＝6.8Hz,1H),3.81(d,J＝14.5Hz,1H),3.49(dq,J＝14.2,7.0Hz,1H),3.30(s,3H),3.16(dq,J＝14.6,7.3Hz,1H),3.03(d,J＝14.5Hz,1H),1.26(d,J＝6.8Hz,3H),1.20(t,J＝7.1Hz,3H).13C NMR(126MHz,CDCl3)δ191.09(s),170.39(s),147.58(s),136.85(s),135.65(s),132.80(s),131.89(s),128.61(s),128.27(s),127.24(s),126.11(s),118.65(s),116.09(s),112.34(s),77.31(s),77.06(s),76.80(s),62.16(s),61.45(s),52.09(s),44.83(s),34.47(s),12.90(s),10.78(s).HRMS(ESI):calcd for C21H22BrNO3Na[M+Na]+:439.3042,found:439.3046。
Example 5
Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, 5-bromo-2-furaldehyde
The product is as follows: chemical formula C19H18BrNO4
Molecular weight: 404.2600
Structural formula (xvi):
Figure BDA0003603331350000092
yield: 68 percent of
1H NMR(500MHz,CDCl3)δ7.80(dd,J＝8.0,1.6Hz,1H),7.36(ddd,J＝8.5,7.1,1.6Hz,1H),6.69(dd,J＝11.1,3.8Hz,1H),6.55(d,J＝8.4Hz,1H),6.00(d,J＝3.2Hz,1H),5.91–5.85(m,1H),4.20(dt,J＝9.9,6.1Hz,1H),3.82(s,3H),3.51–3.35(m,2H),3.18(dd,J＝15.3,7.1Hz,1H),3.10(d,J＝15.4Hz,1H),2.18(dtd,J＝11.4,7.8,3.5Hz,1H),2.01–1.87(m,3H).13C NMR(126MHz,CDCl3)δ190.90(s),171.03(s),152.67(s),148.58(s),135.67(s),129.03(s),119.27(s),117.44(s),116.57(s),112.79(s),111.99(s),111.42(s),77.28(d,J＝6.5Hz),77.05(s),76.79(s),62.51(s),60.22(s),52.67(s),46.62(s),26.03(d,J＝16.7Hz),22.88(s).HRMS(ESI):calcd for C19H18BrNO4Na[M+Na]+:427.2492,found:427.2494。
Example 6
Raw materials: 2-Tetrahydropyrrole-benzoyl-acetic acid methyl ester, 2-quinolinecarboxaldehyde
The product is as follows: chemical formula C24H22N2O3
Molecular weight: 386.4510
Structural formula (xvi):
Figure BDA0003603331350000101
yield: 65 percent of
1H NMR(500MHz,CDCl3)δ7.79(t,J＝7.5Hz,1H),7.77–7.71(m,2H),7.64(t,J＝8.7Hz,1H),7.60–7.53(m,1H),7.40(dt,J＝16.5,4.8Hz,1H),7.25–7.21(m,2H),6.67–6.60(m,1H),6.29(d,J＝8.4Hz,1H),4.34–4.22(m,1H),3.82(s,3H),3.64–3.55(m,1H),3.46(d,J＝13.8Hz,1H),3.37–3.26(m,2H),2.37–2.25(m,1H),2.23–2.13(m,1H),2.10–1.89(m,2H).13C NMR(126MHz,CDCl3)δ191.43(s),171.88(s),157.77(s),148.36(s),147.19(s),135.37(s),134.80(s),128.98(d,J＝15.9Hz),128.72(s),127.36(s),126.73(s),125.78(s),122.89(s),118.47(s),116.30(s),112.62(s),77.29(d,J＝6.3Hz),77.06(s),76.81(s),63.12(s),61.05(s),52.70(s),46.52(s),36.40(s),26.58(s),23.04(s).HRMS(ESI):calcd for C24H22N2O3Na[M+Na]+:409.4402,found:409.4407。
Example 7
Raw materials: 2-tetrahydropyrrole benzoylacetic acid methyl ester, phenylpropargylaldehyde
And (3) a product: chemical formula C23H21NO3
Molecular weight: 359.4250
Structural formula (xvi):
Figure BDA0003603331350000102
yield: 70 percent of
1H NMR(500MHz,CDCl3)δ7.93(t,J＝8.9Hz,1H),7.43–7.36(m,1H),7.22(d,J＝6.1Hz,5H),6.73(t,J＝7.5Hz,1H),6.62(d,J＝8.4Hz,1H),4.28(dt,J＝13.0,6.9Hz,1H),3.89(d,J＝9.9Hz,3H),3.54(dd,J＝16.7,7.6Hz,1H),3.50–3.42(m,1H),2.97(d,J＝17.1Hz,1H),2.91–2.84(m,1H),2.30–2.18(m,2H),2.13–1.93(m,2H).13C NMR(126MHz,CDCl3)δ190.47(s),170.67(s),149.00(s),135.88(s),131.53(s),129.22(s),128.05(s),127.71(s),123.48(s),117.18(s),116.60(s),113.06(s),85.71(s),82.43(s),77.40(s),77.15(s),76.89(s),62.38(s),59.49(s),52.76(s),46.75(s),26.55(s),23.25(s),18.31(s).HRMS(ESI):calcd for C23H21NO3Na[M+Na]+:382.4142,found:382.4145。
Example 8
Raw materials: 4-methoxy-2-tetrahydropyrrole benzoylacetic acid methyl ester, phenylpropargylaldehyde
The product is as follows: chemical formula C24H23NO4
Molecular weight: 389.4510
Structural formula (xvi):
Figure BDA0003603331350000111
yield: 76 percent of
1H NMR(500MHz,CDCl3)δ7.75(d,J＝8.9Hz,1H),7.14–7.07(m,5H),6.20(dd,J＝8.9,2.3Hz,1H),5.83(d,J＝2.2Hz,1H),4.20(dd,J＝9.0,6.3Hz,1H),3.74(s,3H),3.67(s,3H),3.41–3.28(m,2H),2.89–2.80(m,1H),2.77(d,J＝17.2Hz,1H),2.18–2.06(m,2H),1.89(qdd,J＝11.5,9.4,3.2Hz,3H).13C NMR(126MHz,CDCl3)δ189.01(s),170.87(s),166.07(s),150.88(s),131.84–131.02(m),131.28–131.02(m),128.02(s),127.66(s),123.59(s),111.55(s),105.44(s),95.61(s),85.96(s),82.22(s),77.43(d,J＝6.7Hz),77.20(s),76.94(s),62.38(s),59.23(s),55.35(s),52.71(s),46.77(s),26.67(s),23.26(s),18.80(s).HRMS(ESI):calcd for C24H23NO4Na[M+Na]+:412.4402,found:412.4405。
Example 9
Raw materials: 2-Tetrahydropyrrole benzoylacetic acid methyl ester, 3-methylcrotonal
The product is as follows: chemical formula C19H23NO3
Molecular weight: 313.3970
Structural formula (xvi):
Figure BDA0003603331350000112
yield: 66 percent
1H NMR(500MHz,CDCl3)δ7.82–7.76(m,1H),7.41–7.33(m,1H),6.69(dt,J＝15.0,7.5Hz,1H),6.60(d,J＝8.4Hz,1H),5.17(t,J＝7.5Hz,1H),4.23–4.10(m,1H),3.82(s,3H),3.59–3.44(m,2H),2.58–2.48(m,1H),2.42–2.31(m,1H),2.05–1.90(m,3H),1.55(s,4H),1.16(d,J＝18.8Hz,3H).13C NMR(126MHz,CDCl3)δ191.65(s),171.92(s),148.39(s),135.42(s),134.19(s),129.07(s),118.90(s),117.48(s),116.28(s),112.46(s),77.27(d,J＝6.3Hz),77.04(s),76.79(s),62.82(s),60.12(s),52.43(s),46.70(s),26.26(s),25.88(s),24.52(s),23.05(s),17.13(s).HRMS(ESI):calcd for C19H23NO3Na[M+Na]+:336.3862,found:336.3865。
The compounds of the present invention were tested for inhibition of tumor cell proliferation by the conventional MTT method. Three compounds of 2, 3-dihydroquinolin-4-one (example 3, example 6 and example 7) with 5-bromofuryl, 2-quinolinemethyl and phenylethynyl, respectively, were chosen for the experiments. MGC-803 (human gastric cancer cell), HepG2 (human hepatoma cell) and human lung cancer cell strain A549 are selected as cell strains. The culture solution is DMEM + 15% NBS + double antibody, and the anti-tumor drug 5-fluorouracil is used as a control. Inoculating cells into a 96-well plate by using 4000cell/ml cell suspension, wherein the total volume of each well is 192 mu L, culturing for 24h, adding 8 mu L of compound, and acting for 72h by using a medicament; discard the drug-containing culture medium and wash the well plate once with PBS; and adding 100 mu L of MTT solution into the culture solution again, continuously culturing for 4h, removing the culture solution, adding DMSO, detecting the OD value of 570nm by using an MK-2 full-automatic enzyme standard instrument after complete dissolution and color development, calculating the cell survival rate, and calculating the half inhibitory concentration IC 50. The results are shown in Table 3. Experimental results show that the compound has good anti-tumor activity.
TABLE 3
Figure BDA0003603331350000121
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions should be within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present disclosure and the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A 2, 3-dihydroquinolin-4-one bioactive scaffold, having a structural formula:
Figure FDA0003603331340000011
in the formula, R1Is any one of nitrogen heterocycle and ethyl; r2Is any one of nitrogen heterocycle and methyl; r3Is any one of hydrogen atom and methoxyl; r4Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.
2. A method of synthesizing a 2, 3-dihydroquinolin-4-one bioactive scaffold as recited in claim 1, comprising the step of:
uniformly mixing 2-aminobenzoyl methyl acetate compounds and formaldehyde compounds in a molar ratio of 1:1.2-1:1.5 in a solvent, and reacting at 80-120 ℃ to obtain 2, 3-dihydroquinolin-4-one compounds;
wherein, the structural formula of the 2-aminobenzoyl methyl acetate compound is as follows:
Figure FDA0003603331340000012
wherein R is1Is any one of nitrogen heterocycle and ethyl; r2Is any one of nitrogen heterocycle and methyl; r3Is any one of hydrogen atom and methoxyl;
wherein, the structural formula of the formaldehyde compound is as follows:
Figure FDA0003603331340000013
wherein R is4Is any one of aryl, heteroaryl, aliphatic substituent, alpha, beta-unsaturated aryl or alpha, beta-unsaturated aliphatic substituent and alpha, beta-phenyl alkynyl.
3. The method of synthesis according to claim 2, wherein the solvent is ethanol or 1, 2-dichloroethane; preferably, the solvent is 1, 2-dichloroethane.
4. The synthesis process according to claim 2, characterized in that the solvent is used in an amount such that: adding 0.5-2.0mL of solvent into 0.1 mol of 2-aminobenzoyl methyl acetate compound; preferably, 1mL of the solvent is added per 0.1mmol of the methyl 2-aminobenzoylacetate-based compound.
5. The synthesis method according to claim 2, wherein a catalyst is added before the reaction, and the catalyst is a Bronsted acid and a Lewis acid; preferably, the catalyst is Sc (OTf)3。
6. The synthesis method according to claim 5, wherein the catalyst is used in an amount of 10 to 20 mol%.
7. The synthesis process of claim 5, wherein a catalyst support is added prior to the reaction, the catalyst support being
Figure FDA0003603331340000021
And (3) a molecular sieve.
8. The synthesis method according to claim 7, wherein the catalyst carrier is used in an amount of 6 to 7 times the mass of the formaldehyde-based compound.
9. The synthesis process according to claim 2, characterized in that before the reaction, a base is added, which is piperidine, in an amount of 4-6 mol%.
10. Use of a 2, 3-dihydroquinolin-4-one bioactive scaffold synthesized by a method according to any one of claims 2 to 9 in an anti-cancer medicament.
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